Fibrous proteins, which serve a structural role in organisms, have a rodlike conformation which can include regular α-helical, triple helical, or β-sheet/β-turn secondary structure. Fibrous proteins include collagen, keratin, myosin, tropomyosin and fibrinogen.
A number of disorders are characterized by inappropriate deposition of fibrous proteins. In addition to aberrant fibrous protein deposition, some fibrotic disorders, such as sclerotic disorders and, in particular, systemic sclerosis (scleroderma), show aberrant inflammatory and vascular activity. Systemic sclerosis is characterized by diffuse fibrosis of the skin, blood vessels, gastrointestinal tract, lungs, heart, and kidneys; and vascular abnormalities in the skin and articular structures (The Merck Manual of Diagnosis and Therapy, Internet Edition, Section 5, Chapter 50, Diffuse Connective Tissue Disease, Systemic Sclerosis, 2001). Patients suffer from skin thickening, pain, swelling, and stiffness of the fingers and knees, esophageal dysfunction, pulmonary hypertension, and renal failure. Thirty to 60% of scleroderma patients typically develop some restrictive lung disease within the first 3-5 years of disease (Steen V D et al. (1994) Arthritis Rheum 37: 1283; Black C M et al. (1996) In Systemic Sclerosis. Clements P J and Furst D E, eds. Williams & Williams, Baltimore, Md. pp. 299-332; Griedinger E L et al. (1998) Chest 114: 801). A subset of these patients, about 15-20% of all scleroderma patients, develops severe interstitial fibrosis (Steen V D et al. (1994) supra). Patients who do not have lung inflammation have lower risk for progressive lung fibrosis (Silver R M et al. (1990) Am J Med 88: 470; White B et al. (2000) Annals Int Med 132: 947). Lung inflammation occurs early in the course of scleroderma lung disease (Harrison N K et al. (1991) Am Rev Respir Dis 144: 706).
The etiology of systemic sclerosis is not well defined, but an activated immune system (especially T cells) and overproduction and accumulation of collagen and other extracellular matrix proteins are observed (See The Merck Manual, 2001 supra). T cells are believed to be important in the development of tissue damage in patients with systemic sclerosis. Activated T cells are present very early in the course of the disease and dominate the inflammatory infiltrates in tissues of patients with systemic sclerosis (White, B. (1996) Scleroderma, Rheumatic Disease Clinics of North America, Vol. 22 (4):695-708). When activated, T cells regulate functions of many hematopoietic and nonhematopoietic cells, including vascular cells and fibroblasts (White, B. (1996) supra).
Therapies for systemic sclerosis, and in particular for treating scleroderma interstitial lung disease, all have shortcomings. A number of small case series has suggested that therapy with cyclophosphamide may improve the outcome in scleroderma patients with lung inflammation, with stabilization of lung function and improved survival. However, cyclophosphamide has many significant side effects, including global bone marrow suppression which is accompanied by an increased risk of infection, hemorrhagic cystitis, and increased risk of malignancy. Many patients are hesitant to take cyclophosphamide therapy because of these risks. In addition, about 25% of patients with lung inflammation who receive cyclophosphamide do not respond significantly to the treatment, displaying continued decline in lung function (White, B. (2000) supra).
Other vital organs can be critically impaired by fibrosis and the associated inflammation. For example, hepatic fibrosis occurs as a response to hepatocellular necrosis or injury; collagen accumulation leads to hepatic cell atrophy and disruption of hepatic blood flow (Berkow, R. et al. (1992) The Merck Manual of Diagnosis and Therapy, Internet Edition, Section 6, Chapter 68, Fibrosis, Etiology, Pathogenesis).
Accordingly, there exists a need for improved modalities for preventing and treating conditions characterized by aberrant fibrosis such as systemic sclerosis, and in particular, conditions involving fibrosis of vital organs, e.g., lung or liver.